Immunosuppression is a conserved driver of tuberculosis susceptibility.

( ) causes 1.6 million deaths a year . However, no individual mouse model fully recapitulates the hallmarks of human tuberculosis disease. Here we report that a comparison across three different susceptible mouse models identifies -induced gene signatures that predict active TB disease in humans significantly better than a signature from the standard C57BL/6 mouse model. An increase in lung myeloid cells, including neutrophils, was conserved across the susceptible mouse models, mimicking the neutrophilic inflammation observed in humans . Myeloid cells in the susceptible models and non-human primates exhibited high expression of immunosuppressive molecules including the IL-1 receptor antagonist, which inhibits IL-1 signaling. Prior reports have suggested that excessive IL-1 signaling impairs control . By contrast, we found that enhancement of IL-1 signaling via deletion of IL-1 receptor antagonist promoted bacterial control in all three susceptible mouse models. IL-1 signaling enhanced cytokine production by lymphoid and stromal cells, suggesting a mechanism for IL-1 signaling in promoting control. Thus, we propose that myeloid cell expression of immunosuppressive molecules is a conserved mechanism exacerbating disease in mice, non-human primates, and humans.